The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. The mission of Project 1 is to determine the perimenopausal bioenergetic phenotypes most at risk for developing bioenergetics predictive of AD pathology; delineate the mechanistic pathways involved in development of the at-AD-risk phenotype; and assess the impact of ovarian hormone and nutritional interventions on expression of bioenergetic biomarkers of AD. Utilizing rodent models of human perimenopause. Project 1 will achieve its mission by determining; (1) in Aim 1 the bioenergetic phenotypes induced by the perimenopausal transition, (2) in Aim 2 the mechanisms that generate the at-AD-risk phenotype and (3) in Aim 3 the window of opportunity to prevent bioenergetic at-AD-risk phenotype. To address our hypotheses, we will experimentally determine bioenergetic gene expression across the perimenopausal transition and monitor indicators of mitochondrial function which will include: bioinformatics network analyses of gene expression, in vivo cerebral glucose metabolism and synaptic transmission. Mechanistic analyses will address (1) hypometabolism and cell- specific metabolic profiles, (2) redox control of bioenergetic pathway, and (3) white matter loss. Project 1 collaborates with Projects 2, 3 and 4 to test the hypothesis that decline in brain bioenergetics leads to activation of the inflammatory response in brain (Project 2) which exacerbates mitochondrial function which leads to development of AD pathology (Project 3) and mitochondrial dysfunction is associated with cognitive decline in women assessed through ancillary analyses of the ELITE NIA sponsored clinical trial (Project 4). Outcomes of Project 1 research will include: (1) basic science discovery ofthe bioenergetics ofthe perimenopausal aging transition in brain regions vulnerable to development of AD pathology; (2) mechanistic pathways that lead to decline in bioenergetics in the perimenopausal brain; (3) translational research discovery of the window of opportunity for ovarian hormone intervention to prevent decline in bioenergetics in the perimenopausal brain and (4) clinical associations of bioenergetic gene expression, mitochondrial function in peripheral blood cells and cognitive decline in postmenopausal women.